Project Summary/Abstract: The promise of stem cell-based therapies is currently not being fully realized due to the lack of appropriate pre-clinical animal models. Consequently, there remains a critical need to develop better animal models that better translate results from preclinical research trials to the patient. Scientific advancements addressing this problem have been realized through the identification of a naturally occurring Severe Combined Immuno- Deficient (SCID) line of pigs. The SCID pig model has been preliminarily characterized as both T and B lymphocytes deficient and thus is deficient in adaptive immunity. The pig is known to be an excellent model for human biology due to similarities in size, physiology and genetic code; and this novel SCID model has been successfully engrafted with multiple human cancer cell lines, indicating high potential as an in vivo model for many areas of regenerative medicine testing. We have received multiple requests and interest in obtaining this model. The research areas of these interested scientists spans many areas of regenerative medicine research, from cardiac progenitor cell therapies to cartilage regeneration studies, to the use of mesenchymal stem cells for bone regeneration and wound repair, to improving treatment of graft versus host disease in hematopoietic stem cell (HSC) transplants. A pig SCID model will have a specific positive impact in that it will provide researchers with alternative and comparative models for such stem cell research. Our long-term goal is to create validated SCID models for broad use in preclinical testing of such stem cell based therapies. The specific objectives of this application are to further develop this model for regenerative medicine testing, as well as improve its ability to engraft human cells into the bone marrow so that a human immune system can develop. Such an advanced model could be broadly used for vaccine testing and the study of human-specific pathogens. To maximize the broad use of these models, we will further develop protocols and design and test biocontainment facilities for practical utilization of our current pig lines. Our rationale for the proposed research is that the SCID pig is physiologically and phylogenetically more similar to humans than the mouse and therefore may more accurately reflect how proposed stem cells will survive and function in humans. This project is innovative because a SCID pig model has not been fully developed, and development of such model may result in significantly and rapidly advancing the fundamental knowledge of SCID into translational medicine capable of accelerating regenerative medicine research. With regard to expected outcomes, the successful completion of this project will create multiple genetic resources and associated animal procedures that will be highly desirable for SCID based modeling for research projects focused on the efficacy of stem cell therapeutics. Thus these unique resources are expected to have a significant impact in accelerating the translation of regenerative medicine research into the clinic.